The Role of Epigenetics in Mitochondrial Biogenesis-Mediated Recovery after Spinal Cord Injury

表观遗传学在脊髓损伤后线粒体生物发生介导的恢复中的作用

• 批准号: 10477196
• 负责人: Natalie E Scholpa
• 金额: --
• 依托单位: SOUTHERN ARIZONA VA HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10477196
• 关键词: ADRB2 gene; Address; Adrenergic Agonists; Affect; Age; Agonist; Antioxidants; Area; Behavioral; Biogenesis; Bioinformatics; Biology; Blood Vessels; Caring; Cell physiology; Clinical; Clinical Trials; Communication; Complex; Data; Development; Development Plans; Devices; Disease; Doctor of Philosophy; Epigenetic Process; Event; Exposure to; FDA approved; Female; Financial compensation; Functional disorder; Gene Expression Profiling; Genes; Genetic; Genetic Transcription; Genomics; Goals; Health Care Costs; Healthcare; Healthcare Systems; Human; Individual; Injury; Intensive Care; Investigation; Knowledge; Laboratories; Lesion; Locomotor Recovery; Maintenance; Mediating; Mediator of activation protein; Medical; Mentors; Mitochondria; Modification; Molecular; Mus; Nature; Neurosurgeon; Oral; Oxygen; Pathology; Patients; Pharmacology; Phase; Play; Publishing; Recovery; Rehabilitation therapy; Reporting; Research Personnel; Role; Site; Spinal Cord; Spinal cord injury; Therapeutic; Time; Training; Trauma; United States; United States Department of Veterans Affairs; Veterans; beta-2 Adrenergic Receptors; career; career development; clinical application; cost; disability; educational atmosphere; epigenome; experience; formoterol; improved; in vivo; injury recovery; innovation; loss of function; male; mitochondrial dysfunction; novel strategies; prevent; service member; skills; therapeutic target; treatment group

The goal of this project is to determine the role of epigenetic modifications of mitochondrial genes in the induction of the plateau phase after spinal cord injury (SCI), and to exploit these modifications to promote recovery. SCI is a devastating disorder often resulting in loss of function below the injury site. In recent years, service members have been threatened by more advanced warfare, such as improvised explosive devices, ultimately inducing more severe and complex injuries, including SCI. The devastating and debilitating nature of these injuries has not been lessened. The Department of Veterans Affairs (VA) is the largest healthcare network for individuals suffering from SCI, providing care for 25% of total victims in the United States. Improved therapeutics for the treatment of SCI would greatly benefit not only sufferers, but also the VA healthcare system. SCI is defined by direct trauma to the spinal cord, which disrupts the vasculature, leading to decreased oxygen delivery within the area and reducing the ability of mitochondria to maintain cellular energetics. Thus far, the majority of studies targeting mitochondrial dysfunction following SCI have focused on downstream aspects of mitochondrial function (e.g. antioxidant defenses). Reestablishment of mitochondrial function through pharmacological induction of mitochondrial biogenesis (MB) remains an underexplored but novel strategy. I previously reported that treatment with the mitochondrially biogenic FDA-approved β2-adrenergic receptor agonist formoterol beginning up to 8h after SCI improves spinal cord mitochondrial function, decreases lesion volume and enhances locomotor recovery by 7 days post-injury (DPI). Consistent with other published data, the majority of the improvements observed with formoterol occurred within the first 2 weeks, after which recovery plateaued. A similar effect is observed in humans, with the majority of recovery taking place within the first year then reaching a plateau. The mechanism behind the development of this plateau phase, however, is not fully understood. By determining the mechanism of its formation, the plateau phase could be prevented and/or reversed, potentially allowing for continued recovery following injury. My preliminary studies revealed genetic differences within the injured spinal cord of formoterol-treated mice between the recovery phase (7 DPI) and the plateau phase (15 DPI), namely a decrease in genes associated with mitochondrial function, and a concurrent increase in genes associated with epigenetic modifications. Therefore, I hypothesize that epigenetic alterations contribute to decreased transcription of mitochondrial genes within the spinal cord during the plateau phase, preventing continued recovery of mitochondrial function and limiting the efficacy of formoterol treatment in mice. To address this hypothesis, I propose the following Specific Aims: 1) Further elucidate the genetic profile within the spinal cord during the post-SCI recovery period (7 DPI) and plateau phase (≥15 DPI), with and without formoterol treatment in mice; 2) Elucidate the mechanisms of epigenetic modifications on the transcription of mitochondrial genes during the transition from recovery to plateau phase post-SCI, with and without formoterol treatment; 3) Assess the pharmacological efficacy of inhibiting epigenetic events on MB and recovery post-SCI in vivo, with and without formoterol treatment. Successful completion of this proposal could provide integral information into the recovery plateau observed after SCI. I am using an FDA-approved compound, male and female mice and initiating treatment up to 8h after injury, emphasizing the clinical applicability. This proposal will also directly assess the therapeutic potential of my findings by determining if modulation of epigenetic status improves recovery after injury. My mentoring team has formulated a comprehensive career development plan that includes exposure to a rich educational environment, opportunities to improve oral and written communication skills and mentoring on project and laboratory maintenance to ease transition to independence. This project and training will facilitate the completion of my long-term career goal of becoming and independent VA researcher.

该项目的目的是确定线粒体基因表观遗传修饰在 脊髓损伤（SCI）后高原相的诱导，并利用这些修饰为 促进康复。 SCI是一种毁灭性的疾病，通常导致损伤部位下方的功能丧失。最近 多年来，服务成员受到更高级战争的威胁，例如改善的爆炸性 设备最终诱发了更严重和复杂的伤害，包括SCI。破坏性和衰弱 这些伤害的性质尚未减少。退伍军人事务部（VA）是最大的医疗保健 患有SCI的人的网络，为美国提供了25％的总违规行为。改进 治疗SCI的治疗剂不仅会使患者，而且会使VA医疗保健系统受益。 SCI是通过直接创伤对脊髓的直接创伤来定义的，脊髓破坏了脉管系统，导致氧气减少 在该区域内递送并降低线粒体维持细胞能的能力。那远， SCI后针对线粒体功能障碍的大多数研究都集中在下游方面 线粒体功能（例如抗氧化剂防御）。通过重新建立线粒体功能 线粒体生物发生（MB）的药理学诱导仍然是一种毫无疑问但新颖的策略。 我先前报道说，用线粒体生物源性FDA批准的β2-肾上腺素接收器进行治疗 SCI改善脊髓线粒体功能后，激动剂formoterol最高为8H，降低病变 在伤害后7天（DPI）之前，体积并增强了运动恢复。与其他已发布的数据一致 用福莫特罗观察到的大多数改进发生在前2周内，此后恢复 平稳。在人类中观察到类似的效果，大部分恢复发生在第一年内 然后到达高原。然而，这个高原阶段发展的机制尚未完全 理解。通过确定其形成的机制，可以预防高原阶段和/或 逆转，有可能在受伤后继续恢复。我的初步研究揭示了遗传 在恢复阶段（7 dpi）和 高原阶段（15 dpi），即与线粒体功能相关的基因降低，并并发 与表观遗传修饰相关的基因增加。因此，我假设表观遗传 改变有助于脊髓内线粒体基因的精致转录 高原阶段，防止线粒体功能继续恢复并限制 小鼠的福托赛治疗。为了解决这一假设，我提出了以下特定目的：1）进一步 在SCI后恢复期（7 dpi）和高原阶段阐明脊髓内的遗传特征 （≥15dpi），在小鼠中进行有没有配方剂的治疗； 2）阐明表观遗传学的机制 在从恢复到高原阶段过渡期间线粒体基因转录的修改 SCI后，有和不进行造型酚处理； 3）评估抑制表观遗传学的药物效率 在体内进行MB和SCI后的MB和恢复事件，进行和不接受福莫特罗处理。 该提案的成功完成可以为观察到的恢复高原提供不可或缺的信息 科幻之后。我正在使用FDA批准的化合物，雄性和雌性小鼠，并启动最多8小时的治疗 伤害，强调临床适用性。该建议还将直接评估 我的发现通过确定表观遗传状态的调节是否可以改善受伤后的恢复。 我的心理团队制定了一项全面的职业发展计划，包括接触富人 教育环境，改善口头和书面沟通技巧以及心理的机会 项目和实验室维护以简化过渡到独立性。这个项目和培训将有助于 成为我成为独立VA研究人员的长期职业目标的完成。